Oral route is the most common route of drug administration. The drug delivered by oral administration is usually in the form of powder, tablet or capsule, and is first dissolved in the gastrointestinal fluid along the GI tract and the dissolved drug subsequently permeates through the gastrointestinal membrane. However, oral route is not suitable for many drug molecules because of unacceptably low bioavailability caused by low water solubility, poor gastrointestinal membrane permeability, first pass metabolism, and instability in the gastrointestinal environment.
Soy isoflavones are phytoestrogens with chemical structures and physiological functions that are similar to those of the female hormone, estrogen. Thus, they can relieve estrogen-deficient diseases especially menopausal symptoms including hot flashes, osteoporosis and cardiovascular problems. To date, twelve main isoflavones have been characterized in soy bean or soy bean products including genistein, daidzein, and glycitein (aglycones), and their respective malonyl, acetyl, and glucosyl forms (glucosides) (Apers et al. 2004; Rostagno et al. 2004). Although isoflavones (e.g. Genistein) have been widely used as healthcare products to relieve estrogen-deficient diseases especially menopausal symptoms, their therapeutic effects may be hampered by its poor water solubility. In order to improve its water solubility, some research groups have tried to form complexes between genistein and different carriers such as cyclodextrins (Lee et al. 2007; Stancanelli et al. 2007; Daruhazi et al. 2008) and PEG (Motlekar et al. 2006). However, these methods have limitations such as high residual organic solvent content, the instability of drugs and carriers as well as the safety issues of the carrier materials. Thus, there still remains a need for a process which can produce a dosage form of soy isoflavone with improved water solubility and bioavailability.
A way to increase the dissolution rate of poorly water soluble drugs is through the increase in the total surface area by reducing the drug particle size. Different techniques have been applied for this purpose, including spray drying, freeze-drying, milling, liquid anti-solvent crystallization and precipitation with supercritical fluid. Compared to other techniques, supercritical fluid-based technology has attracted a great deal of attention because of the following four major advantages: (1) controlled particle size and distribution, (2) low cost and environmentally benign properties, (3) no degradation of product due to mechanical or thermal stresses relatively because of the mild operating conditions (Tc=31.1° C., Pc=7.38 MPa), (4) no contamination due to the presence of organic solvents. Among the supercritical fluid based processes for producing fine particles, precipitation with compressed antisolvent (PCA) using supercritical CO2 has attracted a vast amount of attention. U.S. Pat. No. 5,874,029 (Subramaniam; Bala et al. 1999), U.S. Pat. No. 6,319,521 (Randolph; Theodore W. et al. 2001), U.S. Pat. No. 7,332,111 (Grothe; Willy et al. 2008), disclosed PCA process for producing fine particles. However, none of these conventional methods have achieved a significant particle size reduction with proof of improvements in the dissolution rate and bioavailability of the active ingredients being atomized into fine particles. Therefore, there is a need for providing an optimized PCA process to produce a desirable nanoparticle of soy isoflavone with significant particle size reduction and improved dissolution rate/bioavailability suitable for both oral and inhalable administrations.